Variant 7-12337012-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001135924.3(VWDE):c.4534T>C(p.Trp1512Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.65

Variant links:

Genes affected

VWDE (HGNC:21897): (von Willebrand factor D and EGF domains) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

VWDE links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VWDE	NM_001135924.3 linkuse as main transcript	c.4534T>C	p.Trp1512Arg	missense_variant	26/29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2 linkuse as main transcript	c.4189T>C	p.Trp1397Arg	missense_variant	24/27		NP_001333901.1
VWDE	NM_001346973.2 linkuse as main transcript	c.3724T>C	p.Trp1242Arg	missense_variant	24/27		NP_001333902.1
VWDE	NR_144534.2 linkuse as main transcript	n.5356T>C		non_coding_transcript_exon_variant	27/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8 linkuse as main transcript	c.4534T>C	p.Trp1512Arg	missense_variant	26/29	5	NM_001135924.3	ENSP00000275358	P1	Q8N2E2-1
VWDE	ENST00000452576.6 linkuse as main transcript	c.*1298T>C		3_prime_UTR_variant, NMD_transcript_variant	27/30	1		ENSP00000401687
VWDE	ENST00000521169.5 linkuse as main transcript	c.*2912T>C		3_prime_UTR_variant, NMD_transcript_variant	23/26	5		ENSP00000428810

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000641

AC:

AN:

156114

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.4534T>C (p.W1512R) alteration is located in exon 26 (coding exon 26) of the VWDE gene. This alteration results from a T to C substitution at nucleotide position 4534, causing the tryptophan (W) at amino acid position 1512 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.69

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-7.5

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.82

MutPred

0.66

Gain of methylation at W1512 (P = 0.0558);

MVP

0.50

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over